The present disclosure generally relates to acylsulfonamides and processes for their preparation. The disclosure also relates to a kinetically controlled target-guided synthesis approach for the discovery and development of small molecules.
Combinatorial chemistry and parallel synthesis are the tools commonly utilized for lead compound identification and optimization. However, even though in the last two decades combinatorial chemistry and parallel synthesis have gone hand in hand with the dramatic advances of technology for rapid production, handling and screening of large numbers of compounds, they are often accompanied by challenges such as the efficiency of library synthesis, the purity of each library member, and the unambiguous identification of lead compounds in the screening of each library member against a particular biological target. In the last decade, fragment-based lead compound discovery or target-guided synthesis (TGS) approaches have been developed in which the biological target is actively engaged in the design and the synthesis of its own enzyme inhibitory compounds. To date, target-guided synthesis has exclusively been applied for enzymatic targets only. See, e.g., Manetsch et al., Journal of the American Chemical Society 2004, 126, 12809-12818; Sharpless et al., Expert Opin. Drug Discovery 2006, 1, 525-538; and Kolb et al., U.S. Patent Publication No. 2006/0269942.
Among a variety of proteins, the Bcl-2 family of proteins, which consists of both anti- and pro-apoptotic molecules, in particular, can play an important role in the regulation of the intrinsic (mitochondrial) pathway of apoptosis. The anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL, Mcl-1) inhibit the release of certain pro-apoptotic factors from mitochondria, whereas pro-apoptotic Bcl-2 family members, which can be further separated into two subgroups, the multidomain BH1-3 proteins (Bax and Bak) and the BH3-only proteins (e.g., Bad, Bim, and Noxa), induce the release of mitochondrial apoptogenic molecules into the cytosol. Although the precise biochemical mechanisms by which Bcl-2 family proteins exert their influence on cell life and death remains far from clear, the relative ratios of pro- and anti-apoptotic Bcl-2 family proteins determine the ultimate sensitivity or resistance of cells to a wide variety of apoptotic signals.
Evidence has accumulated that the majority of human cancers overexpress the pro-survival Bcl-2 family proteins, which not only contribute to cancer progression by preventing normal cell turnover, but also render cancer cells resistant to current cancer treatments. For example, high levels of Bcl-2 are found in ˜30% to 60% of prostate cancer, ˜60% to 90% of breast cancer, ˜20% to 40% of non-small cell lung cancer, ˜60% to 80% of small cell lung cancer, ˜50% to 100% of colorectal cancer, ˜65% of melanoma, ˜30% of neuroblastomas, and ˜80% of B cell lymphomas. Similarly, Bcl-XL is overexpressed in ˜100% of hormone-refractory prostate cancer, ˜40% to 60% of breast cancer, ˜80% of colorectal cancer, ˜90% of melanoma, ˜90% of pancreatic cancer, and ˜80% of hepatocellular carcinoma. It has been shown that overexpression of Bcl-2 and/or Bcl-XL renders cancer cells resistant to most of the currently available chemotherapeutic drugs as well as radiation therapy. Therefore, it is an attractive strategy to design and develop a new class of anticancer drugs that specifically target the anti- and pro-apoptotic functions of the Bcl-2 family proteins.